Cisapride is a stimulant of gastrointestinal motility which is used for the symptomatic relief of gastroesophageal reflux disease (GORD) and thus is effective as a gastroprokinetic agent. Cisapride is the subject of EP 0 076 530B.
Cisapride is poorly soluble and thus may be administered as a salt, such as the tartrate salt, for oral administration or, alternatively, formulated in a way which increases solubility of the base in an aqueous environment as found in the gastrointestinal tract.
WO 96/14070 concerns extended release formulations comprising cisapride-(L)-tartrate embedded in viscous hydrophilic polymers which release cisapride in a racemic form comprising equal amounts of the diastereomeric salt forms (+)-cisapride-(L) tartrate and (-)-cisapride-(L) tartrate which have equal dissolution rates. The hydrophilic polymers swell in contact with an aqueous environment creating a porous matrix from which the cisapride is gradually released.
Cisapride is currently administered in the form of immediate release tablets containing cisapride as the monohydrate equivalent to 10 mg or 20 mg of cisapride. The dosage regimen (at least initially) is 10 mg four times a day. Furthermore, the drug must be administered 15 min. before meals.
There is a need for a controlled release formulation of cisapride containing 40 mg of cisapride that can be administered once-daily and which is bioequivalent in terms of AUC (area under the curve) to the current standard treatment (10 mg q.i.d.) allowing for direct substitution of the standard treatment.
Furthermore, the release rate of cisapride from the formulation should be such that it delivers a smooth plasma concentration versus time profile with minimal peak to trough variation. The effect of food on the absorption profile should be minimised as should the potential for `dose dumping`. A formulation having all of these features would enhance patient acceptability as well as the safety and tolerability of the formulation relative to the standard treatment.